Astrocyte atrophy induced by L-PGDS/PGD2/Src signaling dysfunction in the central amygdala mediates postpartum depression.

BACKGROUND: Postpartum depression (PPD) is a serious psychiatric disorder that has significantly adverse impacts on maternal health. Metabolic abnormalities in the brain are associated with numerous neurological disorders, yet the specific metabolic signaling pathways and brain regions involved in PPD remain unelucidated. METHODS: We performed behavioral test in the virgin and postpartum mice. We used mass spectrometry imaging (MSI) and targeted metabolomics analyses to investigate the metabolic alternation in the brain of GABAAR Delta-subunit-deficient (Gabrd-/-) postpartum mice, a specific preclinical animal model of PPD. Next, we performed mechanism studies including qPCR, Western blot, immunofluorescence staining, electron microscopy and primary astrocyte culture. In the specific knockdown and rescue experiments, we injected the adeno-associated virus into the central amygdala (CeA) of female mice. RESULTS: We identified that prostaglandin D2 (PGD2) downregulation in the CeA was the most outstanding alternation in PPD, and then validated that lipocalin-type prostaglandin D synthase (L-PGDS)/PGD2 downregulation plays a causal role in depressive behaviors derived from PPD in both wild-type and Gabrd-/- mice. Furthermore, we verified that L-PGDS/PGD2 signaling dysfunction-induced astrocytes atrophy is mediated by Src phosphorylation both in vitro and in vivo. LIMITATIONS: L-PGDS/PGD2 signaling dysfunction may be only responsible for the depressive behavior rather than maternal behaviors in the PPD, and it remains to be seen whether this mechanism is applicable to all depression types. CONCLUSION: Our study identified abnormalities in the L-PGDS/PGD2 signaling in the CeA, which inhibited Src phosphorylation and induced astrocyte atrophy, ultimately resulting in the development of PPD in mice.

Allopregnanolone in the peripartum: Correlates, concentrations, and challenges - A systematic review.

BACKGROUND: Allopregnanolone (ALLO) is a metabolite of progesterone and a neuroactive steroid hormone. As a positive allosteric modulator of gamma-aminobutyric acid (GABA) receptors, ALLO seems to have antidepressant and anxiolytic effects, and was therefore approved as a specific medication for the treatment of postpartum depression in 2019. Despite the growing number of publications investigating ALLO levels, results on the biological and psychological correlates in the peripartum period remain inconsistent, possibly due to methodological challenges regarding measurement. To date, however, there is no systematic review examining the correlates, concentrations, and challenges in measuring ALLO in peripartum women. METHOD: A systematic literature search of PubMed and PsycINFO was conducted in August 2023. Original research articles that measured ALLO concentrations in peripartum women were included. Reports were excluded if they were not original research, included non-human subjects, did not include peripartum women, did not include ALLO measurement as an outcome, included (pharmacological) interventions, constituted method validations, or used the same cohort as another study. RESULTS: The literature search yielded 234 articles, and two articles were identified from other sources. After full-text screening, 19 articles (N = 1401) met the inclusion criteria, of which seven focused on biological correlates of ALLO and 12 on mood correlates. Of the latter, six found no association between ALLO and mood, four found a negative association, and two found a positive association. Overall, the results show an increase in ALLO levels during pregnancy and a decrease after birth, with levels then remaining low until six months postpartum. ALLO was most commonly measured in blood plasma and by gas chromatography-mass spectrometry (GC-MS). A significant matrix effect was found for blood serum and a significant method effect for radioimmunoassays (RIAs). A significant effect of time of measurement was found. CONCLUSION: ALLO measurement shows method and matrix effects. ALLO levels are higher when measured in serum compared to in plasma, and when measured using RIA compared to other methods. Time of measurement, study design, and standardization of measurement also influence the reliability of measurement and the interpretation of results.

Gut microbiota dysbiosis contributes to depression-like behaviors via hippocampal NLRP3-mediated neuroinflammation in a postpartum depression mouse model.

Postpartum depression (PPD) is a severe mental disorder that affects approximately 10---20% of women after childbirth. The precise mechanism underlying PPD pathogenesis remains elusive, thus limiting the development of therapeutics. Gut microbiota dysbiosis is considered to contribute to major depressive disorder. However, the associations between gut microbiota and PPD remain unanswered. Here, we established a mouse PPD model by sudden ovarian steroid withdrawal after hormone-simulated pseudopregnancy-human (HSP-H) in ovariectomy (OVX) mouse. Ovarian hormone withdrawal induced depression-like and anxiety-like behaviors and an altered gut microbiota composition. Fecal microbiota transplantation (FMT) from PPD mice to antibiotic cocktail-treated mice induced depression-like and anxiety-like behaviors and neuropathological changes in the hippocampus of the recipient mice. FMT from healthy mice to PPD mice attenuated the depression-like and anxiety-like behaviors as well as the inflammation mediated by the NOD-like receptor protein (NLRP)-3/caspase-1 signaling pathway both in the gut and the hippocampus, increased fecal short-chain fatty acids (SCFAs) levels and alleviated gut dysbiosis with increased SCFA-producing bacteria and reduced Akkermansia in the PPD mice. Also, downregulation of NLRP3 in the hippocampus mitigated depression-like behaviors in PPD mice and overexpression of NLRP3 in the hippocampal dentate gyrus induced depression-like behaviors in naïve female mice. Intriguingly, FMT from healthy mice failed to alleviate depression-like behaviors in PPD mice with NLRP3 overexpression in the hippocampus. Our results highlighted the NLRP3 inflammasome as a key component within the microbiota-gut-brain axis, suggesting that targeting the gut microbiota may be a therapeutic strategy for PPD.

Antidepressant effects of esketamine via the BDNF/AKT/mTOR pathway in mice with postpartum depression and their offspring.

Postpartum depression (PPD) is a serious mental health problem that can negatively affect future generations. BDNF/AKT/mTOR signaling in the frontal lobe and hippocampus in mice is associated with depression, but its role in mice with PPD and their offspring is unknown. This study was aimed at investigating the effects of esketamine (ESK), a drug approved for treatment of refractory depression, on the BDNF/AKT/mTOR pathway in mice with PPD and their offspring. A model of chronic unpredictable mild stress with pregnancy was used. ESK was injected into postpartum mice, and behavioral tests were conducted to predict the severity of symptoms at the end of lactation and in the offspring after adulthood. Both mice with PPD and their offspring showed significant anxiety- and depression-like behaviors that were ameliorated with the ESK intervention. ESK enhanced exploratory behavior in unfamiliar environments, increased the preference for sucrose, and ameliorated the impaired BDNF/AKT/mTOR signaling in the frontal and hippocampal regions in mice. Thus, ESK may have great potential in treating PPD and decreasing the incidence of depression in offspring.

Postpartum symptoms of anxiety, depression and stress: differential relationships to women's cortisol profiles.

PURPOSE: Women are at high risk of stress, anxiety, and depression during the postpartum but the ways in which these different types of psychological distress are related to cortisol regulation is not clear. We examined the distinct association of each type of distress with women's average cortisol level, cortisol awakening response (CAR), cortisol decline across the day (diurnal slope), and overall amount of cortisol secretion across the day (AUCG). METHODS: At 6 months postpartum, a diverse group of 58 women completed measures of depression, anxiety, perceived stress, and life stressors. Each woman provided 4 salivary samples for cortisol assay from waking to bedtime on each of 2 consecutive days. Linear regressions were used to examine associations of stress, anxiety and depression to each of the 4 cortisol measures, controlling for number of stressful life events. RESULTS: Depressive symptoms were associated with less of a rise in the CAR (ß = -.46, p = 0.01), steeper diurnal slope (ß = .51, p = 0.006), and higher average cortisol level (ß = .42, p = .01). Women who met the clinical cutoff for an anxiety disorder had lower overall cortisol output (ß = -.29, p = 0.03). Stress was not related to any cortisol metric. CONCLUSIONS: Findings suggest that stress is less associated with cortisol alterations in the postpartum than are more severe types of psychological distress. Anxiety and depression may have distinct and opposite profiles of cortisol dysregulation. Results indicate that mental health assessment is critical even in the later postpartum so that interventions can be initiated to reduce emotional suffering and the risk of impaired cortisol regulation.

Blood extracellular vesicles carrying brain-specific mRNAs are potential biomarkers for detecting gene expression changes in the female brain.

The absence of non-invasive tests that can monitor the status of the brain is a major obstacle for psychiatric care. In order to address this need, we assessed the feasibility of using tissue-specific gene expression to determine the origin of extracellular vesicle (EV) mRNAs in peripheral blood. Using the placenta as a model, we discovered that 26 messenger RNAs that are specifically expressed in the placenta are present in EVs circulating in maternal blood. Twenty-three of these transcripts were either exclusively or highly expressed in maternal blood during pregnancy only and not in the postpartum period, verifying the feasibility of using tissue-specific gene expression to infer the tissue of origin for EV mRNAs. Using the same bioinformatic approach, which provides better specificity than isolating L1 cell-adhesion molecule containing EVs, we discovered that 181 mRNAs that are specifically expressed in the female brain are also present in EVs circulating in maternal blood. Gene set enrichment analysis revealed that these transcripts, which are involved in synaptic functions and myelination, are enriched for genes implicated in mood disorders, schizophrenia, and substance use disorders. The EV mRNA levels of 13 of these female brain-specific transcripts are associated with postpartum depression (adjusted p-vals = 3 × 10-5 to 0.08), raising the possibility that they can be used to infer the state of the brain. In order to determine the extent to which EV mRNAs reflect transcription in the brain, we compared mRNAs isolated from cells and EVs in an iPSC-derived brain microphysiological system differentiated for 3 and 9 weeks. We discovered that, although cellular and extracellular mRNA levels are not identical, they do correlate, and it is possible to extrapolate cellular RNA expression changes in the brain via EV mRNA levels. Our findings bring EV mRNAs to the forefront of peripheral biomarker development efforts in psychiatric diseases by demonstrating the feasibility of inferring transcriptional changes in the brain via blood EV mRNA levels.

TOM40 mediates the effect of TSPO on postpartum depression partially through regulating calcium homeostasis in microglia.

AIMS: To assess the effect of the translocator protein 18 kDa (TSPO) on postpartum depression and explore its mechanism. METHODS: Postpartum depression (PPD) mouse model was established, and flow cytometry, immunofluorescence, Western blot analysis, real-time quantitative PCR, adeno-associated virus (AAV), co-immunoprecipitation-mass spectrometry and immunofluorescence co-staining were used to detect the effect of TSPO ligand ZBD-2 on PPD mice. RESULTS: ZBD-2 inhibits the overactivation of microglia in the hippocampus and amygdala of PPD model mice. ZBD-2 not only inhibited the inflammation but also repressed the burst of reactive oxygen species (ROS) and mitochondrial ROS (mtROS). Meanwhile, ZBD-2 protects mitochondria from LPS-induced damages through inhibiting the influx of calcium. ZBD-2 modulated the calcium influx by increasing the level of translocase of the outer mitochondrial membrane 40 (TOM40) and reducing the interaction of TSPO and TOM40. In addition, the effect of ZBD-2 was partially dependent on anti-oxidative process. Knockdown of TOM40 by adeno-associated virus (AAV) in the hippocampus or amygdala dramatically reduced the effect of ZBD-2 on PPD, indicating that TOM40 mediates the effect of ZBD-2 on PPD. CONCLUSIONS: TOM40 is required for the effect of ZBD-2 on treating anxiety and depression in PPD mice. This study reveals the role of microglia TSPO in PPD development and provides the new therapeutic strategy for PPD.

Divergent Transcriptomic Effects of Allopregnanolone in Postpartum Depression.

Brexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic efficacy across numerous neuropsychiatric disorders. Given ALLO's beneficial effects on mood in women with PPD compared to healthy control women, we sought to characterize and compare the cellular response to ALLO in women with (n = 9) or without (n = 10, i.e., Controls) past PPD, utilizing our previously established patient-derived lymphoblastoid cell lines (LCLs). To mimic in vivo PPD ALLO-treatment, LCLs were exposed to ALLO or DMSO vehicle for 60 h and RNA-sequenced to detect differentially expressed genes (DEGs, pnominal < 0.05). Between ALLO-treated Control and PPD LCLs, 269 DEGs were identified, including Glutamate Decarboxylase 1 (GAD1), which was decreased 2-fold in PPD. Network analysis of PPD:ALLO DEGs revealed enriched terms related to synaptic activity and cholesterol biosynthesis. Within-diagnosis analyses (i.e., DMSO vs. ALLO) detected 265 ALLO-induced DEGs in Control LCLs compared to only 98 within PPD LCLs, with just 11 DEGs overlapping. Likewise, the gene ontologies underlying ALLO-induced DEGs in PPD and Control LCLs were divergent. These data suggest that ALLO may activate unique and opposing molecular pathways in women with PPD, which may be tied to its antidepressant mechanism.

Intrinsically dysregulated cellular stress signaling genes and gene networks in postpartum depression.

Postpartum depression (PPD) is a leading cause of morbidity and mortality among women. Clinically, the administration and withdrawal of supraphysiologic estradiol and progesterone (E2 + P) can cause affective symptom reoccurrence in women with a history of PPD, but not matched controls. To investigate the cellular basis underlying this differential affective response, lymphoblastoid cell lines (LCLs) were derived from women with and without past PPD and compared transcriptomically in hormone conditions mimicking pregnancy and parturition: supraphysiologic E2 + P-addback; supraphysiologic E2 + P-withdrawal; and no added E2 + P (Baseline). RNA-sequencing identified unique differentially expressed genes (DEGs) in all hormone conditions, but the majority tended to be downregulated in PPD and observed in E2 + P-addback. Two of these DEGs were evolutionarily conserved cellular stress regulators: IMPACT, an integrative response protein maintaining translational homeostasis, and WWTR1, a transcriptional coactivator in the 'Hippo' pathway mediating cell proliferation and survival. Correspondingly, significant gene network modules were linked to cell cycle progression, estrogen response, and immune dysregulation, suggesting innate differences in intracellular signaling in PPD. In certain hormone conditions, PPD LCLs displayed increased GATA3 expression (an upstream regulator of IMPACT and WWTR1) and differentially phosphorylated eiF2α (the ultimate downstream target of IMPACT). Taken together, these transcriptomic data primarily implicate innately dysregulated cellular responses as potentially influencing mood and/or escalating PPD risk. Furthermore, the intrinsic downregulation of IMPACT's translation and WWTR1's transcription networks may suggest a novel link between PPD and a compromised ability to maintain homeostasis in the context of cellular stress occurring during pregnancy and parturition.

Resveratrol alleviates postpartum depression-like behavior by activating autophagy via SIRT1 and inhibiting AKT/mTOR pathway.

BACKGROUND: Postpartum depression (PPD) causes maternal mortality, and has a high disability rate. In recent years, studies have suggested the Sirt1 gene to be involved in the pathogenesis of depression. Resveratrol (RSV), an activator of Sirt1, has been investigated in depressive behavior. However, its effect on PPD remains to be thoroughly elucidated. METHODS: We employed a mice model with bilateral oophorectomy combined with hormone-simulated pregnancy to assess postpartum depression-like behavior. The behavioral tests were performed 2 days after the withdrawal of estradiol benzoate. RSV was administered subcutaneously to the PPD model mice. Several behavioral tests were executed, including the open field test, forced swimming test, and tail suspension test. Western blot analyses and immunofluorescence staining were used to evaluate protein expression levels of SIRT1, autophagy markers, and the AKT/mTOR. RESULTS: Postpartum depressive-like behavior was triggered following the withdrawal of estradiol benzoate after hormone-stimulated-pregnancy. RSV improved postpartum depressive-like behavior of mice via its upregulation of the SIRT1 and autophagy markers, such as Beclin1, ATG5 and LC3B. Also, the downregulation of the p62 protein expression was observed. More importantly, we also detected the inhibition of phosphorylated AKT and mTOR in the hippocampus of postpartum depressive-like mice. CONCLUSION: RSV could alleviate postpartum depression-like behavior in mice by stimulating the SIRT1, induce autophagy and inhibit the AKT/ mTOR signaling pathway.

Paeoniflorin exhibits antidepressant activity in rats with postpartum depression via the TSPO and BDNF­mTOR pathways.

Postpartum depression (PPD) is the most common type of puerperal mental syndrome and affects maternal physical and mental health and even the growth and development of infants. Paeoniflorin exerts a potential antidepressive effect; however, the functional roles and potential mechanisms of paeoniflorin in PPD are still largely unknown. PPD rat models were prepared by withdrawing hormone­simulated pregnancy (HSP), and subjects were treated with paeoniflorin and fluoxetine or plasmids. The sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST) were used to monitor depression­like behavior in rats. A radioimmunoassay was utilized for estradiol (E2) and progesterone (P) measurements. ELISA was performed to detect serum corticosterone (Cor), hippocampal allopregnanolone (Allo), IL­1ß and TNF­α levels. Expression of the E2 receptors ERα and ERß was detected by qPCR. Western blotting was used to detect TSPO, BDNF and mTOR phosphorylation. Paeoniflorin drastically increased the sucrose preference of rats while decreasing the immobility time in the FST and TST in PPD models. Moreover, paeoniflorin intervention upregulated serum E2, hippocampal Allo, ERα, and ERß levels but degraded P, serum Cor, IL­1ß, TNF­α and ERα/ERß levels. Mechanistically, paeoniflorin promoted TSPO and BDNF­mTOR pathway activation in PPD rats. Furthermore, suppression of TSPO or the BDNF­mTOR pathway partially reversed the effects of paeoniflorin on depression­like behaviors, hormone levels, and inflammatory cytokine release. Paeoniflorin may improve symptoms of PPD by regulating the TSPO and BDNF­mTOR pathways, indicating that paeoniflorin may be an effective anti­PPD and antidepressant drug, providing evidence for the future treatment of PPD.

Transcriptome-wide association study for postpartum depression implicates altered B-cell activation and insulin resistance.

Postpartum depression (PPD) affects 1 in 7 women and has negative mental health consequences for both mother and child. However, the precise biological mechanisms behind the disorder are unknown. Therefore, we performed the largest transcriptome-wide association study (TWAS) for PPD (482 cases, 859 controls) to date using RNA-sequencing in whole blood and deconvoluted cell types. No transcriptional changes were observed in whole blood. B-cells showed a majority of transcriptome-wide significant results (891 transcripts representing 789 genes) with pathway analyses implicating altered B-cell activation and insulin resistance. Integration of other data types revealed cell type-specific DNA methylation loci and disease-associated eQTLs (deQTLs), but not hormones/neuropeptides (estradiol, progesterone, oxytocin, BDNF), serve as regulators for part of the transcriptional differences between cases and controls. Further, deQTLs were enriched for several brain region-specific eQTLs, but no overlap with MDD risk loci was observed. Altogether, our results constitute a convergence of evidence for pathways most affected in PPD with data across different biological mechanisms.

Prospective Investigation of Glutamate Levels and Percentage Gray Matter in the Medial Prefrontal Cortex in Females at Risk for Postpartum Depression.

BACKGROUND: The substantial female hormone fluctuations associated with pregnancy and postpartum have been linked to a greater risk of developing depressive symptoms, particularly in high-risk women (HRW), i.e. those with histories of mood sensitivity to female hormone fluctuations. We have shown that glutamate (Glu) levels in the medial prefrontal cortex (MPFC) decrease during perimenopause, a period of increased risk of developing a major depressive episode. Our team has also demonstrated that percentage gray matter (%GM), another neural correlate of maternal brain health, decreases in the MPFC during pregnancy. OBJECTIVE: To investigate MPFC Glu levels and %GM from late pregnancy up to 7 weeks postpartum in HRW and healthy pregnant women (HPW). METHODS: Single-voxel spectra were acquired from the MPFC of 41 HPW and 22 HRW using 3- Tesla in vivo proton magnetic resonance spectroscopy at five different time points. RESULTS: We observed a statistically significant interaction between time and group for the metabolite Glu, with Glu levels being lower for HRW during pregnancy and early postpartum (p<0.05). MPFC %GM was initially lower during pregnancy and then significantly increased over time in both groups (p<0.01). CONCLUSION: This investigation suggests that the vulnerability towards PPD is associated with unique fluctuations of MPFC Glu levels during pregnancy and early postpartum period. Our results also suggest that the decline in MPFC %GM associated with pregnancy seems to progressively recover over time. Further investigations are needed to determine the specific role that female hormones play on the physiological changes in %GM during pregnancy and postpartum.

Ameliorative effect of SIRT1 in postpartum depression mediated by upregulation of the glucocorticoid receptor.

Recent evidence has confirmed the association of glucocorticoid receptor (GR) gene variants with the "stress" endocrine axis in postpartum depression (PPD). Sirtuin 1(SIRT1) is an NAD+-dependent histone deacetylase and transcriptional enhancer of GR. However, to date, the function of the SIRT1 gene in the regulation of GR expression in PPD remains to be fully determined. A hormone-stimulated pregnancy (HSP) and subsequent "postpartum" withdrawal of estrogen was employed to mimic the fluctuations in estradiol associated with pregnancy and postpartum. We confirmed that estradiol benzoate withdrawal (EW)-rats displayed depression- and anxiety-like behaviors. These behavioral dysfunctions are associated with attenuated expression of SIRT1 and GR in the hippocampus. To assess the role of SIRT1, as well as its regulatory target directly, a selective SIRT1 activator (SRT2104) was infused into the hippocampus of EW-rats. We found that pharmacological activation of hippocampal SIRT1 blocks the development of depression-related, but not anxiety-related, phenotypes of PPD. In addition, the activation of SIRT1 leads to an increase in hippocampal GR expression in EW-rats. We further confirmed that SIRT1 physically interacts with GR in a glucocorticoid-dependent manner. Taken together, our results suggest that neuropathology in PPD is caused, at least in part, by the inhibition of the SIRT1-GR signaling pathway. Elevating SIRT1 levels, either pharmacologically or through other means, could represent a therapeutic strategy for PPD.

The combination of fluoxetine and environmental enrichment reduces postpartum stress-related behaviors through the oxytocinergic system and HPA axis in mice.

Gestational stress can increase postpartum depression in women. To treat maternal depression, fluoxetine (FLX) is most commonly prescribed. While FLX may be effective for the mother, at high doses it may have adverse effects on the fetus. As environmental enrichment (EE) can reduce maternal stress effects, we hypothesized that a subthreshold dose of FLX increases the impact of EE to reduce anxiety and depression-like behavior in postpartum dams exposed to gestational stress. We evaluated this hypothesis in mice and to assess underlying mechanisms we additionally measured hypothalamic-pituitary-adrenal (HPA) axis function and brain levels of the hormone oxytocin, which are thought to be implicated in postpartum depression. Gestational stress increased anxiety- and depression-like behavior in postpartum dams. This was accompanied by an increase in HPA axis function and a decrease in whole-brain oxytocin levels in dams. A combination of FLX and EE remediated the behavioral, HPA axis and oxytocin changes induced by gestational stress. Central administration of an oxytocin receptor antagonist prevented the remediating effect of FLX + EE, indicating that brain oxytocin contributes to the effect of FLX + EE. These findings suggest that oxytocin is causally involved in FLX + EE mediated remediation of postpartum stress-related behaviors, and HPA axis function in postpartum dams.

A Primer on DNA Methylation and Its Potential to Impact Maternal Depression Risk and Assessment During Pregnancy and the Postpartum.

Depression onset during and after pregnancy is prevalent and associated with significant implications for maternal, child, and family health. Although environmental risk factors important to the expression of pregnancy-related depression are well known, knowledge of the genetic underpinning is limited. Given the joint contribution of environmental and genetic factors to depression risk liability, DNA methylation presents itself as an ideal biomarker to investigate basic mechanisms and opportunities for translational research to care for pregnancy-related depression health outcomes. This article is an introduction to DNA methylation and its potential to serve as a marker of depression risk during pregnancy and the postpartum. This commentary discusses current clinical uses of DNA methylation-based testing and how it may be applied to perinatal depression clinical care and management.

Transdermal delivery of breakthrough therapeutics for the management of treatment-resistant and post-partum depression.

For the first time in over three decades, the year 2019 saw the approval of two new classes of antidepressants: Spravato™ esketamine intranasal spray for treatment-resistant depression, and Zulresso® brexanolone infusion against post-partum depression. Although both therapies were granted "breakthrough" designations, topical application of both drugs could offer several advantages over their current routes of administration. However, delivery of their high therapeutic doses (0.5 mg/kg ketamine in 1 h; 90 µg/kg/h brexanolone over 52 h) is unachievable by conventional means. We evaluated physical enhancement techniques such as iontophoresis, microneedle-treatment, and ablative laser for the rapid delivery of ketamine. Additionally, the sustained delivery of brexanolone across microporated skin employing chemical enhancers and novel microemulsions was also accomplished. The target therapeutic flux of ketamine after skin pre-treatment with laser (534.51 ± 146.93 µg/cm2), and the application of anodal iontophoresis (681.93 ± 74.35 µg/cm2) on ablated skin, was observed within one hour. Microporation of skin using laser was more effective than microneedles, for the delivery of ketamine as well as brexanolone. The developed microemulsions resulted in significantly higher transdermal delivery across laser-treated skin. Although brexanolone demonstrated higher solubility in the w/o microemulsion (21.31 ± 0.14 mg/mL) than the o/w microemulsion (10.69 ± 0.09 mg/mL), percutaneous absorption from the o/w microemulsion (6.04 ± 0.16%) was significantly higher than the w/o microemulsion (1.92 ± 0.02%).

Maternal Separation Model of Postpartum Depression: Potential Role for Nucleus Accumbens Dopamine D1-D2 Receptor Heteromer.

Postpartum depression is a mood disorder with a distinct neurobiological and behavioural profile occurring during and after the postpartum period. Dopamine pathways in the limbic regions of the brain such as the nucleus accumbens (NAc) have been shown to be involved in the etiology of depressive disorders. Selective activation of the dopamine D1-D2 receptor heteromer has been demonsrated to cause depressive- and anxiogenic-like behaviours in rats. The maternal separation model involving three hour daily maternal separation (MS) from pups on PPD 2-15 on anxiety-, depression- and anhedonia-like behaviors in the dams was investigated, together with plasma corticosterone, oxytocin and D1-D2 heteromer expression in the NAc core and shell in non-MS and MS dams. Depression, anxiety and anhedonia-like behaviours were measured using the forced swim test, elevated plus maze and sucrose preference test, respectively. In comparison to non-MS controls, MS dams displayed slightly higher depressive and anxiety-like behaviours with no difference in anhedonia-like behaviours. The MS dams displayed significantly increased care of pups after their retrieval with higher bouts of nursing, lower latency to nurse, lower bouts of out nest behaviour and decreased self-care. There was no significant alteration in D1-D2 heteromer expression in NAc core and shell between mothers of either group (MS, non-MS) or between postpartum rats and nonpregnant female rats, remaining higher than in male rats. This data provides evidence for the maternal separation model in producing a postpartum depression-like profile, but with maternal resilience able to modify behaviours to counteract any potential deleterious consequences to the pups.

Mating and parenting experiences sculpture mood-modulating effects of oxytocin-MCH signaling.

The two hypothalamic neuropeptides oxytocin and melanin concentrating hormone (MCH) share several physiological actions such as the control of maternal care, sexual behavior, and emotions. In this study, we uncover the role for the oxytocin-MCH signaling pathway in mood regulation. We identify discrete effects of oxytocin-MCH signaling on depressive behavior and demonstrate that parenting and mating experiences shape these effects. We show that the selective deletion of OXT receptors from MCH neurons increases and decreases depressive behavior in sexually naïve and late postpartum female mice respectively, with no effect on sexually naïve male mice. We demonstrate that both parenting experience and mood-regulating effects of oxytocin-MCH are associated with synaptic plasticity in the reward and fear circuits revealed by the alterations of Arc expressions, which are associated with the depressive behavior. Finally, we uncover the sex-dependent effects of mating on depressive behavior; while the sexual activity reduces the basal levels of depressive behavior in male mice, it reduces in female mice evoked-depression only. We demonstrate that the oxytocin-MCH pathway mediates the effects of sexual activity on depressive behavior. Our data suggest that the oxytocin-MCH pathway can serve as a potential therapeutic target for the treatment of major depression and postpartum mood disorders.

LncRNA Gm14205 induces astrocytic NLRP3 inflammasome activation via inhibiting oxytocin receptor in postpartum depression.

Postpartum depression (PPD) is a kind of mental disorder characterized by persistent low emotions in puerperium. The most significant physiological change in postpartum is lactation which is regulated by oxytocin receptor (OXTR). However, whether OXTR is related to pathological process of PPD and the potential mechanism still remain unclear. In the present study, we prepared hormone-simulated pregnancy (HSP)-induced PPD mouse model and found that the protein level of OXTR in hippocampus of PPD model mice was down-regulated and Nod-like receptor protein 3 (NLRP3) inflammasome was activated. We identified five long non-coding RNAs (lncRNAs) related to PPD by transcriptome sequencing, including three up-regulated and two down-regulated. The five lncRNAs were associated with the signaling pathway of OXTR according to the bioinformatics analysis. Furthermore, we focused on one of the five lncRNAs, Gm14205, and found that it targeted OXTR which inhibited astrocytic NLRP3 inflammasome activation in hippocampal primary astrocytes. These findings illustrate that OXTR has protective effects in PPD by inhibiting NLRP3 inflammasome activation and provides a new strategy for targeting lncRNA Gm14205 in the pathogenesis of PPD.